Identification of cell cycle as the critical pathway modulated by exosome-derived microRNAs in gallbladder carcinoma

Abstract

Gallbladder cancer (GBC), the most common malignancy in the biliary tract, is highly lethal malignant due to seldomly specific symptoms in the early stage of GBC. This study aimed to identify exosome-derived miRNAs mediated competing endogenous RNAs (ceRNA) participant in GBC tumorigenesis. A total of 159 differentially expressed miRNAs (DEMs) was identified as exosome-derived miRNAs, contains 34 upregulated exo-DEMs and 125 downregulated exo-DEMs based on the expression profiles in GBC clinical samples downloaded from the Gene Expression Omnibus database with the R package. Among them, 2 up-regulated exo-DEMs, hsa-miR-125a-3p and hsa-miR-4647, and 5 down-regulated exo-DEMs, including hsa-miR-29c-5p, hsa-miR-145a-5p, hsa-miR-192-5p, hsa-miR-194-5p, and hsa-miR-338-3p, were associated with the survival of GBC patients. Results of the gene set enrichment analysis showed that the cell cycle-related pathways were activated in GBC tumor tissues, mainly including cell cycle, M phase, and cell cycle checkpoints. Furthermore, the dysregulated ceRNA network was constructed based on the lncRNA-miRNA-mRNA interactions using miRDB, TargetScan, miRTarBase, miRcode, and starBase v2.0., consisting of 27 lncRNAs, 6 prognostic exo-DEMs, and 176 mRNAs. Together with prognostic exo-DEMs, the STEAP3-AS1/hsa-miR-192-5p/MAD2L1 axis was identified, suggesting lncRNA STEAP3-AS1, might as a sponge of exosome-derived hsa-miR-192-5p, modulates cell cycle progression via affecting MAD2L1 expression in GBC tumorigenesis. In addition, the biological functions of genes in the ceRNA network were also annotated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Our study promotes exploration of the molecular mechanisms associated with tumorigenesis and provide potential targets for GBC diagnosis and treatment.

Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA

“…Moreover, STEAP3-AS1 caused the expression of its neighboring STEAP3 in a m 6 A modification-dependent manner, which activated Wnt/β-catenin signaling to support CRC progression. Importantly, recent in silico analysis of a serum exosome-derived ceRNA network has identified STEAP3-AS1 as an independent prognostic predictor of glioblastoma and gallbladder cancer [ 48 , 49 ], further proving its clinic value as a promising biomarker for cancers. Therefore, further studies elucidating the functions of secreted STEAP3-AS1 in CRC progression may expand its applications for early detection or prediction of drug response in CRC patients.…”

Integration of single-nucleus and exosome RNA sequencing dissected inter-cellular communication and biomarkers in pancreatic ductal adenocarcinoma

“…This finding suggests a potential role of hsa-miR-4647 as a messenger in the tumor microenvironment. A recent study revealed hsa-miR-4647 was one of two significantly upregulated miRNAs in gallbladder carcinoma and associated with patients’ unfavorable prognosis [36] , suggesting hsa-miR-4647 could be a promising target for developing novel treatment modality for gallbladder carcinoma.…”

Circulating Exosome Cargoes Contain Functionally Diverse Cancer Biomarkers: From Biogenesis and Function to Purification and Potential Translational Utility

“…Wang et al recently demonstrated that the analysis of miRNA targets from exosomes (i.e., purified from urine), when compared with traditional TaqMan qPCR technology, was significantly more accurate and sensitive for the detection of low concentrations (i.e., <100 copies/µL) [ 316 ]. However, although Bio-Rad offers a large array of mRNA-based detection using their ddPCR instrument, they have not established a standardized protocol for the analysis of miRNAs, and the only available protocols are from published studies [ 317 , 318 ]. The protocol of Hindson et al suggests that using ddPCR with TaqMan probes improved the day-to-day reproducibility by 7-fold, as seen by a 37–86% decrease in the coefficient of variation, compared to standard qPCR [ 315 ].…”

“…Cellular proliferation is a critical aspect to tumor progression, which commonly is a result of the deregulation of cell-cycle related proteins [ 316 ], and is a known hallmark of cancer [ 22 ]. Research studies have demonstrated that tumor-derived exosomal miRNAs can regulate cancer cell proliferation by targeting cell cycle-associated proteins and signaling proteins [ 317 ]. For example, in colorectal cancer, miR-200b is transferred between adjacent cancer cells, where it directly targets 3′-UTRs of p27 and Rho Family GTPase 3 (RND3), two proteins involved in cell cycle regulation [ 318 , 319 ], leading to their downregulation, which in turn induces proliferation in recipient cells [ 320 ].…”